Historical Development of the Concept of Controlling Cardiac Arrhythmias by Lengthening

Repolarization: Particular Reference to Sotalol Bramah N. Singh, MD, DPhil

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From the Division of Cardiology, Veterans Administration Medical Center of West Los Angeles, and the Department of Medicine, the University of California at Los Angeles School of Medicine, Los Ange- les, California. This study was supported in part by grants from the M&xl Research Services of the Veterans Administration and the American Heart Association of the Greater Los Angeles Affiliate.

Address for reprints: Bramah N. Singh, MD. Section of Cardiology 691/l I I E. Wadsworth Veterans Administration Hospital, Wilshire and Sawtelle Boulevards, Los Angeles, California 90073.

poundhaseffectsidellthltothoseofttn?levo- isomeratthesamedfug cioncemtraUon8. In high concenbm sotdol hIdbits the inward sodium cwwlthltdoesnotaffectthehwardskwcddun currenLltprolongsrepolarixat&mbyinMbithgthe delayedredisrpoturiunarrent,withamodest effectonthehwardmcUfkr.Afterintravenousor oral addldstratkn h humans, sotabl slows the heartrateandbMmodalumdMion dprdongs therefractotyperkdintheatrkvcntriadunade. 7hseeffectsarecheessmt&Myto~bkdcadeand are sin&r to those produ~I by most heart rate- redudng/3#odcerr.mdassIIIactionsofrotakl anreflectedinthe -ofthem- action potential duratkn accompaded by major in- creaseshtherefractoryperiodsintheaMa,ven- trkks, His-Rrkinje system, and in the bypass tractsinboththere~and~adedi- reCthS.ThsredWg~OCCWindependantlyOf~ bdodde.Thaavai~dataonthephannacody- Mlll&dSktChph~SiOhgk~OfSOwd suggestthatths&ug’sactionshouldresultinthe acuteaml~ylactkumtrolofawidev&etyof supraventdahr and venWudar arr)lythmiis.

(Am J cadiollS9O,65:3A-llA)

T he electrophysiologic concept that cardiac ar- rhythmias may be aborted by lengthening the repo- larization phase of the cardiac action potential is

not new. Not long after quinidine was introduced into therapeutics, Lewis et al ‘J described its clinical use in atria1 fibrillation and suggested that it acted by increas- ing the refractoriness of cardiac muscle. While being consistent with the idea that atria1 fibrillation was based on a “circus” movement in the atria, the suggestion was also appealing since the most readily measurable effect of quinidine was the prolongation of the QT interval on the surface electrocardiogram.

No further advances in understanding how quinidine exerted its beneficial effects in controlling arrhythmias were made for 3 decades. The electrical activity of the heart could then be studied by applying the microelec- trode technique to isolated cardiac muscle. In the 195Os, a number of investigators,34 particularly Vaughan Wil- liams,s showed that quinidine, in clinically meaningful concentrations, had the dominant effect of depressing the

THE AMERICAN JOURNAL OF CARDIOLOGY JANUARY 2,199O 3A

maximal rate of rise of the cardiac action potential rather than lengthening repolarization. Conduction velocity was markedly slowed, while only the terminal portion of repo- larization was modestly lengthened. There was little ef- fect on the plateau phase of the action potential. Thus, it appeared that quinidine had little effect on the absolute refractory period; it could, however, influence the effec- tive refractory period by 2 distinct mechanisms. First, as shown by Weidmann,j the drug shifted the curve relating the maximal rate of rise of the action potential to the membrane voltage in the hyperpolarizing direction. This effect was similar to that produced by low-sodium media. Thus, a critical time-dependent recovery of the sodium carrier mechanism was necessary before the next propa- gated action could be elicited in response to an applied extrastimulus Second, Weidmann’ found that the car- diac membrane needed to repolarize to a certain minimal voltage before a response to a stimulus could be obtained. Therefore, interventions that prolonged the action poten- tial duration were likely to lengthen cardiac refractori- ness. These 2 ways in which cardiac refractoriness can be altered have since been designated as time- and voltage- dependent mechanisms. A careful analysis of the action of quinidine in terms of its concentration-effect relations has shown that its major influence is on depolarization rather than repolarization. In the decade that followed the aforementioned classic observations in the microelec- trode laboratory, the major focus was essentially on the time-dependent mechanism for an increase in refractori- ness as an antiarrhythmic action.8

The question of whether lengthening the effective re- fractory period by prolonging the cardiac action potential itself (without an associated change in the rate of rise of the action potential) might be a discrete antiarrhyth- mic mechanism became clouded by the reports of sud- den deaths that complicated the long QTc-interval syn- dromes9~i0 Schwartzii reviewed the subject, and Sura- wicz and Knoebell* recently discussed the circumstances in which lengthened QTc interval is associated with an enhanced tendency for the occurrence of atypical ventric- ular tachycardia. However, there appears to have been less emphasis on the clinical instances in which lengthen- ing the cardiac action potential has been associated with a reduced probability of cardiac arrhythmias.

Such clinical entities are nevertheless important be- cause they may provide models elucidating the potential mechanisms whereby prolonging cardiac repolarization might constitute an antiarrhythmic effect. Interest re- cently burgeoned in this area, undoubtedly because amio- darone, the dominant electrophysiologic action of which is to lengthen the cardiac action potential during chronic administration, has been found to be an unusually potent agent for controlling most cardiac arrhythmias.i3 Vari- ous lines of evidence recently converged to indicate that the lengthening of the action potential duration provides an important mechanism for controlling cardiac arrhyth- mias.i4 Because this subject was discussed at length in a recent monographi and in an editorial,*6 only the salient features will be considered.

4A THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65

LENGTHENING OF ACTION POTENTIAL DURATION AS AN ANllARRRYlHMlC MECHANISM

As early as 1955, Weidmann3*7 clearly established the voltage dependence of the heart’s refractory period. He showed that in Purkinje fibers under voltage-clamp con- ditions, the membrane potential needed to return to at least -55 mV (after a driven action potential) before another action potential could be elicited. The electro- physiologic implications of this observation are obvious. Thus, physiologic, pharmacologic or pathologic interven- tions tending to shorten the time course of repolarization would, of necessity, abbreviate the refractory period of cardiac muscle and would likely be arrhythmogenic. This has been clearly established for anoxia, halothane and acetylcholine (in atria1 muscle), all of which accelerate repolarization; they all shorten the refractory period and are known to be arrhythmogenic or cause fibrillatory perturbations. For example, atria1 fibrillation can be pro- duced predictably by an atria1 extrastimulus during con- tinuous vagal stimulation.”

However, if one delayed attainment of a minimal level of the membrane voltage needed to generate a second action potential in response to an extrastimulus by inter- fering with processes that normally govern the repolariza- tion rate, the refractory (both the absolute as well as the effective) periods of cardiac muscle would be correspond- ingly prolonged, an antiarrhythmic mechanism.

It should be emphasized that such a change may occur entirely independently of any alteration in cardiac depo larization and conduction velocity. However, it would produce a number of discrete electrophysiologic and ino- tropic effects. First, in pacemaker tissues and other fibers with potential for spontaneous automaticity, lengthening the action potential duration will delay attaining the max- imal diastolic potential. The onset of the next spontane ous diastolic depolarization will be similarly retarded. Thus, the threshold voltage will be reached later and the cycle length of the tachycardia (if automatic) will be prolonged. Second, in nonpacemaker tissues, the in- creases in the action potential duration and in the voltage- dependent refractoriness will slow the tachycardia (re- gardless of its mechanism) or may make it less readily sustained. Moreover, in the case of ventricular tachycar- dia, prolonging the cycle length may prevent the accelera- tion of the tachycardia with a reduction in its tendency to deteriorate into ventricular fibrillation. Such an effect on repolarization, in the case of an intervention that has no significant depressant effect on conduction velocity, is unlikely to lead to reentrant excitation. However, this is likely to hold true only if the lengthening of the action potential duration is uniform, so that the tendency toward focal reexcitation from heterogeneity in repolarization and refractoriness resulting from nonuniform alterations in the action potential durations is avoided.

Finally, the issue of whether lengthening the cardiac action potential duration might affect cardiac contractile force is important. Experimental and clinical data sug- gest that antiarrhythmic agents that lengthen cardiac

repolarization are not negatively inotropic.‘8 There is evi- dence that many of them may exert a positive inotropic action.19 These properties are particularly useful clinical- ly because the patients with life-threatening ventricular arrhythmias have the greatest need for aggressive phar- macologic therapy and the most compromised ventricular function.20

Numerous observations indicate that lengthened car- diac repolarization may be associated with enhanced con- tractility. For example, Kavaler2’ showed that sustained depolarization led to increased tension development in isolated heart muscle. This was confirmed by Morad and Trautwein,22 who studied the relation between the action potential duration and contraction in mammalian cardiac muscle. Therefore, it was interesting when Singh and Vaughan Williams23 showed that, despite the fact that sotalol is a /3 blocker, it did not exert a depressant effect on contractility and, in fact, in some preparations it ex- hibited a frankly positive inotropic effect in feline papil- lary muscle (Fig. 1). This was consistent with the obser- vation of Kaumann and Olson,24 who found that sotalol not only augmented isometric contractions in papillary muscle but also produced long-lasting aftercontractions as a function of increases in the duration of the intracellu- larly recorded action potentials (Fig. 2). In vivo, the posi- tive inotropic effects of sotalol are more difficult to dem- onstrate because such effects may be offset by the con- comitant /3 blockade induced by the drug. However, Brooks et alZ5 reported that intravenously administered sotalol did not significantly depress systemic hemody- namics in patients with cardiac failure, in contrast to the well-known depressant effects of conventional P-blocking agents. Orally administered sotalol has been found to be reasonably well tolerated by patients with low left ven- tricular ejection fractions26,27; rarely does the drug aggra- vate heart failure in such patients. It appears that when it does, the withdrawal of the sympathetic drive by the drug outweighs its potential intrinsic positive inotropic actions. As indicated elsewhere, all or nearly all so-called class 111 antiarrhythmic drugs have a benign hemody- namic profile, even in patients with congestive cardiac

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CLINICAL ANTIARRRYTHMIC CORRELATES OF PROLONGED CARDIAC REPOLARlZAllON

For many years, certain clinical situations have been known to be associated with a reduced incidence of cardi- ac arrhythmias. For example, hypocalcemia homoge- neously lengthens the QT interval of the electrocardio- gram and arrhythmogenicity in hypocalcemic syndromes

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THE AMERICAN JOURNAL OF CARDIOLOGY JANUARY 2.1990 SA

is rare unless complicated by hypokalemia. Furthermore, reducing serum calcium in certain situations (e.g., glyco- side intoxication) may correct dysrhythmias. Perhaps hy- perthyroidism is the most striking example of a clinical entity in which changes in the action potential duration appear correlated with the tendency for arrhythmias to develop; in such cases a marked shortening of the action potential duration of the atria has been reported2* and may be related to the frequent paroxysmal or sustained atria1 fibrillation that responds to antithyroid treatment. Conversely, in hypothyroidism, arrhythmias of any kind are uncommon. The major electrophysiologic effect of deficient thyroid hormone on cardiac muscle is “isolated” prolongation of the action potential duration with depres- sion of phase 4 depolarization in the sinus node.28q29 How- ever, the latter effect may not be caused entirely by lengthening the action potential duration in the sinus node, as there is a downregulation of @ receptors in hypo- thyroidism. The slowing of the sinus frequency may be due in part to adrenergic antagonism secondary to hypo- thyroidism, with a depressant effect on phase 4 depolar- ization. Conversely, Amsdorf and Childers,M using atria from hyperthyroid rabbits, showed that the effective re- fractory period was much shorter than in those that were euthyroid. It is known that phase 4 depolarization is markedly steepened in hyperthyroidism.

These observations on altered thyroid state and the incidence of cardiac arrhythmias may also be related to recent observations linking the stability of sinus rhythm in patients with paroxysmal atria1 fibrillation to the dura- tion of the atria1 action potential determined by intracavi- tary suction electrodes. I9 For example, in patients who underwent electrical conversion to sinus rhythm, the re- lapse rate to atria1 fibrillation was significantly higher in those with shorter action potential durations.31 Thus, these observations clearly suggest that drug-induced lengthening of the myocardial action potential duration, by whatever mechanism, should reduce the probability of cardiac fibrillation. The issue about hypothyroidism, as an example of a clinical situation with a reduced proba- bility of cardiac fibrillation from an apparently potent class III antiarrhythmic action, has recently come into sharp focus because of growing evidence that the funda- mental mechanism of action of amiodarone on repolari- zation might be mediated through a competitive T3 an- tagonism in the myocardium.32

Although this issue is important in the development of class III agents that act in a similar manner to amioda- rone, the effects of sotalol clearly differ from those of amiodarone. Nevertheless, they share 2 features, namely, an antiadrenergic effect associated with a reduction in heart rate and the marked prolongation of the action potential duration and refractoriness in various cardiac fibers.

DEVELOPMENT OF THE PHARMACOLOGIC CONCEPT OF CLASS III ANllARRRWtMlC ACTION: FOCUS ON SOTALOL

While investigating the properties of a number of p antagonists, Singh and Vaughan Williamsz3 and Singh3) found that the &blocking drug sotalol (MJ 1999), be-

6A THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65

sides having the propensity to block B receptors competi- tively, lengthened the intracellularly measured action po tentials in mammalian myocardial fibers (Fig. 1) and prolonged the QTc interval of the surface electrocardio gram in anesthetized guinea pigs. By inference, the drug prolonged the effective refractory period. Sotalol also protected experimental animals from ventricular librilla- tion due to cardiac glycoside intoxication. The overall effects of the drug could not be explained on the basis of /3 blockade alone or by inhibition of the fast-sodium chan- nel. Unlike quinidine or procainamide, sotalol produced no significant changes in depolarization. Thus, it was believed at that time that sotalol exhibited electrophysio- logic properties that were unique. It was postulated that the simple lengthening of the action potential duration constituted a significant and discrete mechanism (the so- called class III) for the control of cardiac arrhyth- mias.23*33 Recent experimental34 and clinica12”*27 observa- tions tend to vindicate these earlier, somewhat theoretical expectations.

There are now a growing number of pharmacologic agents that might exert their major antiarrhythmic ac- tions by selectively lengthening cardiac repolarization. Until recently, the most significant compounds in this class included sotalol and its isomers, amiodarone35 and its metabolite (desethylamiodarone), N-acetylprccaina- mide, bretylium, pranolium, clofilium and melperone. Numerous newer compounds, such as sematilide, E- 403 1, and UK 68,798, among others, now are at varying stages of pharmacologic characterization and clinical evaluation. Structurally and pharmacologically, these agents are diverse. One may therefore expect significant differences with respect to their antiarrhythmic potency, phannacokinetic properties, side-effect profiles, proar- rhythmic tendencies (especially torsades de pointes) and overall clinical efficacy. However, they do share many common features with respect to their hemodynamic and electrophysiologic effects, an understanding of which may provide further insights into the nature of antiar- rhythmic actions.

Only the properties of sotalol will be discussed as a preamble to this international symposium. The main pur- pose here is to bring together, within a convenient and a relatively brief format, the evolving role of this unique /3 blocker, the electrophysiologic properties of which formed the basis for the concept of controlling cardiac arrhythmias by prolonging cardiac repolarization, as was suggested 20 years ago.23

SOTALOL AS A BROAD-SPECTRUM ANTlARRRYlHMIC COMPOUND: ELECTROPRYSIOLOGIC BASIS

In delineating the overall properties of sotalol, it is essential to define those aspects of its antiarrhythmic actions that are caused by its B-blocking properties and those that stem from its property of lengthening cardiac repolarization. Both features constitute integral compo- nents of the drug’s overall antiarrhythmic actions.

b-blod&g potwy ot sotd& Unlike other para- substituted j3 blockers, such as atenolol and metoprolol, sotalol is not cardioselective, nor does it exhibit intrin-

100 ms 10-s lo3 W

sic sympathomimetic activity or local anesthetic ac- tions.23s33Q36 However, numerous in vitro and in vivo stud- ies have clearly established its /?-blocking propensity.3w The commercially available preparation is the racemic mixture of d- and I-sotalol, the dextroisomer having less than one-fiftieth the activity of the levocompound.44

In isolated tissues, sotalol shifts the agonist dose-re- sponse curve to the right33~38*4zA8 in a parallel fashion. In the formal analysis of the differences between proprano- 101 and sotalol as B antagonists, values of j3-blocking po tency for propranolol of about 8.7 and of 6.4 for sotalol have been reported, reflecting a marked difference in the relative potencies of the 2 B blockers.38*43 However, such a 1 00-fold difference in the blocking actions of the 2 com- pounds has not always been demonstrated. Some stud- &36 have shown that in vitro sotalol was one-tenth to one- fiftieth as potent as propranolol. The marked difference between the in vitro and in vivo blocking potencies of sotalol is not completely understood but has been attrib uted to a low lipid solubility, which is balanced by good absorption and high metabolic stability of the drug.

tion in the upstroke velocity of the action potential by sotal at high concentrations. Concentration-dependent depression effects on the upstroke velocity of the action potential are shown in Figure 3.

The property of lengthening the cardiac action poten- tial exhibited by sotalol cannot be attributed to its actions as a @ blocker. Although some lengthening of the myocar- dial action potential duration has been reported in rabbits and in humans chronically treated with a number of 0 blockers,51q52 the magnitude of such changes has been trivial compared with that found with sotalol or amioda- rone. It has not been consistently verified. Therefore, the

In intact anesthetized animals and in conscious hu- mans, the potency ratio between sotalol and propranolol appears to be 1:3 or 1:2 to 3.3U3 However, sotalol exerts a nonadrenergically mediated positive inotropic ef- f~t,*WW.38,39 lth a ough a weak one, which may influ- ence the precise determination of its 8-blocking propensi- ty against standard agonists such as isoprenaline.

Cddu akdmfhyw affects of sotab& It is of historical interest that sotalol was introduced as a /3 blocker in the early 1 960s,37 but its unique electrophysio- logic actions were not appreciated for many years. The initial electrophysiologic studies, reported by Singh and Vaughan WiIliams23 and by Strauss et al,42 indicated that in all cardiac tissues studied, the drug increased the duration of the action potential in a concentration-depen- dent fashion. There was a concomitant lengthening of the _ effective and the absolute refractory period. There was no Ftwm4uhct4d~~ d&mdl-$oto- change in the upstroke velocity of the phase zero of the ldaum~~of~- action potential except when concentrations were 1 Oe4 M lhmmb~~an~dIr2bomusmmmrtkn

or greater. Several investigators49*50 reported the reduc- - - r,lhdCOl.(Adq#~@tOtrom JACC.Y

THE AMERICAN JOURNAL OF CARDIOLOGY JANUARY 2,199O 7A

A s-UM: coNrRoulR8 ARRRYTIIMIAS WHR SoTAla

prolongation of the action potential duration induced by muscle. The data agree with the observations of Shima- sotalol is unlikely to be due to /3 blockade. This is now tori et aJs5 who examined the effects of 5 different /3 supported by our recent observations that the dextro- blockers (including sotalol) on sinoatrial conduction time isomer of the drug (nearly devoid of P-blocking property) in isolated blood-perfused canine atria. In contrast to the exerts an identical effect (see Fig. 4) on repolarization, as depressant effects of propranolol, sotalol had no signifi- does Lsotal01.~ These experimental observations are in cant effect on sinoatrial conduction. accord with the clinical observations: The intravenous mfelctsenmemk~- ofsotabianditsste- injection of the dextroisomer of sotalol in humans had reoi-: At concentrations equal to or less than 1 Om4 little or no @-blocking effect compared with the racemic M, Carmeliet49 found that the main electrophysiologic mixture; however, the repolarization effects (i.e., on the effect of sotalol and its isomers was to prolong the action QTc interval of the electrocardiogram) of the dextro- potential duration (Fig. 3). At higher concentrations, the isomer and racemic compound were comparable over the action potential duration was shortened and V,,, signifi- same drug dose range.53 cantly reduced because of the inhibition of the tetrodotox-

Differences between the actions of propranolol, the in-sensitive inward sodium (“window”) current. The volt- reference @ blocker, and sotalol should be emphasized. age-clamp studies of Carmeliet49 indicated that lengthen- For example, Nakaya et aP4 examined the effects of ing the action potential duration by sotalol may be due to propranolol (0.3 to 30 PM) and sotalol (3 to 300 PM) in a substantial reduction in the delayed rectifier current canine Purkinje fibers and ventricular muscle fibers using (ik; see Fig. 5) associated with a small decrease in the standard microelectrode techniques. Propranolol short- inward rectifier current (ikl). ened the action potential duration in Purkinje fibers but These electrophysiologic effects raise 2 theoretical had little or no effects in ventricular muscle; in contrast, possibilities. First, the lengthening of repolarization will sotalol produced a concentration-dependent increase in delay the inactivation of the slow-calcium channel (with- the action potential duration in both tissues. Further- out effect on the magnitude of the peak current), which more, propranolol decreased the maximal rate of rise of will produce both a net increase in the intracellular calci- the action potential, whereas sotalol had no effect on this urn per beat and an increase in myocardial contractility. parameter except at very high concentrations of the drug, This is consonant with the findings of Kaumann and emphasizing the relative selectivity of sotalol for altering Olson24 and Singh, 33 who reported a positive inotropic repolarization in rather than depolarization of cardiac effect due to sotalol in feline papillary muscle associated

A

8s

8A THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65

THE AMERICAN JOURNAL OF CARDIOLOGY JANUARY 2. 1990 9A

with markedly lengthened action potential duration. In the case of the dextroisomer of sotalol, such an effect is likely to be more pronounced because it will not be atten- uated by associated @-receptor blockade. Second, inhibi- tion of the outward K currents by sotalol and its isomers will lengthen the refractory period. Roth isomers of sota- 101 are thus likely to exert antiarrhythmic actions. The differences in the antiarrhythmic effects of the 2 isomers will permit the separation of the net effects due to p blockade and those due, as it were, to “pure” class III electrophysiologic actions.

Chical ekfrophysiofogk effects of sofafok The clinical effects of sotalol agree with those found in isolat- ed tissues and in intact animals. Electrophysiologic stud- ies using intravenous drugs have established that sotalol lengthens the monophasic action potential in atria and ventricles in humanss2.5”.57 and increases the effective refractory period in atria, ventricle, atrioventricular node and bypass tracts while lengthening the intranodal but not the infranodal conduction time.2”.27.5X”’ These prop erties differ from those of conventional /3 blockers, which have little or no effect on atrial, ventricular and bypass tract effective refractory periods.(j2 The studies of Nade- manee et a127 are in agreement with these findings. Intravenous sotalol lengthened the effective refractory period in atria (+24.6%; p <O.Ol), atrioventricular node (+24.9%; p <O.Ol) and ventricle (+14.9%; p <O.Ol); it significantly lengthened sinus node recovery time QTc and AH but not the HV interval. The effective refractory period of the His-Purkinje system also lengthened after the intravenous administration of sotalol in patients un- dergoing programmed electrical stimulation of the heart.63 Very similar overall electrophysiologic data have been reported by Touboul et a16” and Rorggrefe et al,64 the overall effects being accounted for by summed effects of /3 blockade and those due to the lengthening of the action potential duration without a change in depolariza- tion.

Conymbnofsotakdandprafwmofol,acuteversus chronk eftceb: Creamer et aF5 compared the acute and the chronic effects of propranolol and sotalol in conven- tional equiactive @blocking doses of the 2 antagonists in 8 patients with permanent programmable pacemakers. They found sotalol prolonged the QTc interval by 6.5% after intravenous administration and by 1 I .5% after 4 weeks of oral therapy. There was no change in the QRS duration, and the entire increase in repolarization was therefore due to a lengthening of the JT interval. The prolongation of the QT and JT intervals was related to plasma concentrations of the drug, but a significant rela- tion was not established in this study. It was interesting that the QT lengthening was greater during chronic ther- apy despite somewhat lower serum levels of the drug.

After propranolol therapy, there was no change in the QT or JT intervals and, although there was a minor tendency for the QTc to increase after chronic therapy, this did not reach statistical significance. Thus, the data provide further confirmation that the lengthening of the QTc induced by sotalol is not due to its antiadrenergic property. Creamer et al 6s further showed that neither

drug affected the pacing threshold of the ventricle after intravenous drug administration.

These findings clearly indicate a combination of @- blocking (class II) and class III actions, a combination that is likely to attribute a broad-spectrum antiarrhyth- mic effect to sotalol and a side-effect profile that are essentially predictable on the basis of these 2 fundamen- tal actions.

ELECTROPHYSJOLOGIC AND ANTlARRtlYl’RMlC CORRELATES Of SOTALOL ACTION

There have been numerous experimenta123*33~66-7’ and clinica17z-76 reports documenting a broad range of antiar- rhythmic effects in the case of dl-sotalol. The spectrum of its effects in arrhythmias is wider than that of convention- al /3 blockers.23 Other reports in this symposium proceed- ings discuss the clinical effects from recent investigations. The salient experimental findings relevant to the clinical effects of the drug will be discussed briefly here.

In a model of postmyocardial infarction arrhythmias in conscious dogs, Cobbe et a16* found that ventricular arrhythmias were prevented by sotalol in 11 of 19 studies (58%) compared with I of 14 (7%) with metoprolol, which does not lengthen the action potential duration. The salutary effect of sotalol could be correlated with lengthening the refractory period of the infarct zone, whereas metoprolol had no effect on this parameter, indi- cating that the antiarrhythmic effect of sotalol was not mediated solely through /3 blockade. These observations are also consistent with the findings of Marshall et al,” who found that giving sotalol intravenously significantly increased the ventricular fibrillation threshold of both normal as well as ischemic myocardium in the anesthe- tized rat, whereas metoprolol had no effect on the ventric- ular fibrillation threshold in the normal myocardium and merely prevented the decrease in ventricular fibrillation threshold after coronary artery occlusion. Again, these findings indicate the antitibrillatory and antiarrhythmic actions of sotalol in a variety of animal models, as empha- sized by Patterson and Lucchesi.‘” The major effect ap- pears to be mediated through the lengthening of the ac- tion potential duration.

Although our data clearly show that the dextroisomer is equipotent with the levoisomer and with the racemic mixture in prolonging the effective refractory period, the data dealing with the antiarrhythmic actions of d-sotalol have been limited.78

However, Lynch et al” recently found that 8 mg/kg of intravenous cumulative doses of the levo- as well as the dextroisomer suppressed induction of ventricular tachy- cardia in their conscious-canine ischemic model of sud- den death in 50?& of the dogs. At this dose, only the l- sotalol exerted an antiadrenergic effect such as lengthen- ing the PR interval of the surface electrocardiogram, but both isomers produced equivalent increases of 15 to 20% in the ventricular effective refractory period.

Culling et al79 found that the drug prevented ventricu- lar arrhythmias associated with myocardial ischemia and reperfusion in the isolated buffer-perfused model of the

A 8-M: CONTNWUNG ARNNYlHMlASWilH SOTMOL

guinea-pig heart. In this preparation, ischemia was pro- duced by reduction of flow to 10% for 30 minutes fol- lowed by reperfusion. However, the beneficial effect on the arrhythmia could not be accounted for by alterations in the measured electrophysiologic parameters, such as refractoriness or the time course of the monophasic action potentials. During myocardial &hernia, sotalol has been shown to elevate myocardial pH in the canine heart,*O and the drug’s effect on its so-called class III action is not negated by elevated extracellular potassium.*’

Finally, there are data that suggest that the antilibril- latory effects of sotalol are not confined to ventricular tissue. Bertrix et a182 measured the fibrillation threshold in the canine ventricle and atria concurrently with the amplitude and duration of the monophasic action poten- tial, effective refractory period, the conduction time in the contractile fibers, and the fibrillation rate once fibrilla- tion had been triggered. Sotalol increased the fibrillation threshold in association with increases in the duration of the action potential and the effective refractory period. The fibrillation rate slowed but conductive time did not change. The overall changes were more striking in the case of the atria (than in the ventricles) in which vulnera- bility to fibrillation had been enhanced by acetylcholine (presumably by reversing the cholinergically mediated shortening of the action potential duration and refractori- ness). Sotalol antagonized the changes induced by acetyl- choline. Experimental data thus provide a compelling basis for the antiarrhythmic and antitibrillatory effects in a broad spectrum of supraventricular and ventricular ar- rhythmias.

coNcLusloNs The experimental and clinical data indicate that sota-

101, the prototype of class III antiarrhythmic drugs, exhib- its electrophysiologic characteristics that represent summed effects of blocking @ receptors and that block potassium channels in a variety of myocardial cells. Therefore, unlike conventional /3 antagonists, sotalol pro- longs the refractory period in the atria, ventricles, His- Purkinje system, and the bypass tracts of the heart in addition to lengthening the refractory period in the atrio- ventricular node, slowing the heart rate and delaying intranodal conduction, effects that can be related to the block of adrenergic impulse traffic in the heart. The salu- tary clinical effects of the compound therefore reflect its dual action and emphasize the significance of its major class II as well as its class III actions.

The expanding clinical experience with sotaiol as an antiarrhythmic agent is appropriate to the experimental and clinical electrophysiologic effects of this unique /?- blocking activity. Unlike conventional ~-blocking drugs, dl-sotalol has been found effective in lengthening the anterograde effective refractory period of the bypass tracts in the Wolff-Parkinson-White syndrome and in preventing reinduction of ventricular tachycardia in ex- perimental animals and in humans. These observations, consistent with the additional antiarrhythmic actions of dl-sotalol compared with those of other p blockers, may be due to its propensity to lengthen repolarization and

iOA THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65

refractoriness in cardiac muscle. Compared with amioda- rone, sotalol is a simpler compound electrophysiological- ly. It exerts similar electrophysiologic actions after intra- venous and chronic oral administration. It is therefore likely to be clinically useful in the acute and prophylactic control of a wide variety of supraventricular and ventricu- lar arrhythmias.

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THE AMERICAN JOURNAL OF CARDIOLOGY JANUARY 2.1990 1lA